Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex
| Autor: | Pamela J. Focia, P. Charles Lin, Ann Hye Ryong Shim, Heli Liu, Xiaolin He, Xiaoyan Chen |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2010 |
| Předmět: |
Platelet-derived growth factor
Protein Conformation Receptor Protein-Tyrosine Kinases Molecular Conformation Immunoglobulin domain Plasma protein binding Biology Crystallography X-Ray Receptor tyrosine kinase Receptor Platelet-Derived Growth Factor beta chemistry.chemical_compound Protein structure Animals Humans Platelet-Derived Growth Factor Multidisciplinary Biological Sciences Recombinant Proteins Cell biology chemistry Biochemistry biology.protein Thermodynamics Signal transduction Peptides Hydrophobic and Hydrophilic Interactions Platelet-derived growth factor receptor Protein Binding Signal Transduction |
| Popis: | Platelet-derived growth factors (PDGFs) and their receptors (PDGFRs) are prototypic growth factors and receptor tyrosine kinases which have critical functions in development. We show that PDGFs share a conserved region in their prodomain sequences which can remain noncovalently associated with the mature cystine-knot growth factor domain after processing. The structure of the PDGF-A/propeptide complex reveals this conserved, hydrophobic association mode. We also present the structure of the complex between PDGF-B and the first three Ig domains of PDGFRβ, showing that two PDGF-B protomers clamp PDGFRβ at their dimerization seam. The PDGF-B:PDGFRβ interface is predominantly hydrophobic, and PDGFRs and the PDGF propeptides occupy overlapping positions on mature PDGFs, rationalizing the need of propeptides by PDGFs to cover functionally important hydrophobic surfaces during secretion. A large-scale structural organization and rearrangement is observed for PDGF-B upon receptor binding, in which the PDGF-B L1 loop, disordered in the structure of the free form, adopts a highly specific conformation to form hydrophobic interactions with the third Ig domain of PDGFRβ. Calorimetric data also shows that the membrane-proximal homotypic PDGFRα interaction, albeit required for activation, contributes negatively to ligand binding. The structural and biochemical data together offer insights into PDGF-PDGFR signaling, as well as strategies for PDGF-antagonism. |
| Databáze: | OpenAIRE |
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